Laboratory and Field Evaluation of Biodegradable Polyesters for Sustained Release of Isometamidium and Ethidium

An overview is presented of the results obtained with biodegradable sustained release devices (SRDs) containing a mixture of polymers and either isometamidium (ISMM) or ethidium. Under controlled laboratory conditions (monthly challenge with tsetse flies infected with Trypanosoma congolense) the protection period in SRD treated cattle could be extended by a factor 2.8 (for ethidium) up to 4.2 (for ISMM) as compared to animals treated intramuscularly with the same drugs. Using a competitive drug ELISA ISMM concentrations were detected up to 330 days after the implantation of the SRDs, whereas after i.m. injection the drug was no longer present three to four months post treatment. Two field trials carried out in Mali under heavy tsetse challenge showed that the cumulative infection rate was significantly lower in the ISMM-SRD implanted cattle than in those which received ISMM intramuscularly. Using ethidium SRD, however, contradictory results were obtained in field trials in Zambia and in Mali. The potential advantages and inconvenients of the use of SRDs are discussed and suggestions are made in order to further improve the currently available devices.

A biodegradable drug delivery system for the treatment of postoperative inflammation

Cataract surgery is often performed in patients suffering from associated pathologies. Our goal is to develop a biodegradable drug delivery system (DDS) combined with the artificial intraocular lens (IOL). DDS were manufactured using poly(D,L-lactide-co-glycolide), or PLGA, and were loaded with triamcinolone acetonide (TA). The loading capacity was approximately 1050 microg of TA per DDS. The higher the molecular weight of PLGA (34,000, 48,000 and 80,000Da), the slower was the release of TA in vitro. Cataract surgery was performed on the right eye of rabbits. IOL was inserted with (i) no DDS, (ii) unloaded DDS PLGA48000, (iii) one loaded DDS PLGA48000, (iv) two loaded DDS. The number of inflammatory cells and the protein concentration were measured in the aqueous humor (AH). Unloaded DDS showed good ocular biocompatibility. One DDS PLGA48000 loaded with TA significantly reduced postoperative ocular inflammation. Two loaded DDS PLGA48000 was even more effective in inhibiting such inflammation. On long-term observation (days 63 and 84), reduction of inflammation could be obtained by insertion of one DDS PLGA48000 and a second DDS PLGA80000. Therefore, our "all in one" system is very promising since it could replace oral treatment and reduce the number of intraocular injections

Composite Biodiversity Report

A study to ascertain the biodiversity value of lands on six hospital sites.

Prenatally engineered autologous amniotic fluid stem cell-based heart valves in the fetal circulation.

Prenatal heart valve interventions aiming at the early and systematic correction of congenital cardiac malformations represent a promising treatment option in maternal-fetal care. However, definite fetal valve replacements require growing implants adaptive to fetal and postnatal development. The presented study investigates the fetal implantation of prenatally engineered living autologous cell-based heart valves. Autologous amniotic fluid cells (AFCs) were isolated from pregnant sheep between 122 and 128 days of gestation via transuterine sonographic sampling. Stented trileaflet heart valves were fabricated from biodegradable PGA-P4HB composite matrices (n = 9) and seeded with AFCs in vitro. Within the same intervention, tissue engineered heart valves (TEHVs) and unseeded controls were implanted orthotopically into the pulmonary position using an in-utero closed-heart hybrid approach. The transapical valve deployments were successful in all animals with acute survival of 77.8% of fetuses. TEHV in-vivo functionality was assessed using echocardiography as well as angiography. Fetuses were harvested up to 1 week after implantation representing a birth-relevant gestational age. TEHVs showed in vivo functionality with intact valvular integrity and absence of thrombus formation. The presented approach may serve as an experimental basis for future human prenatal cardiac interventions using fully biodegradable autologous cell-based living materials.

Composite Report (Health Service Reform Programme)

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Composite Report (Health Service Reform Programme)

  This Composite Report on the work of the Action Committees established for Phase I of the Health Reform Programme sets out a brief summary of the issues raised and conclusions reached during Phase I. It is intended as an input to the planning of subsequent phases and should not be regarded as binding in any respect. Click here to download PDF

Prefabrication of composite grafts for long-segment tracheal reconstruction.

OBJECTIVE: To investigate the prefabrication of vascularized mucosa-lined composite grafts intended to replace circumferential tracheal defects. DESIGN: Plane grafts composed of ear cartilage and full-thickness oral mucosa were revascularized by the laterothoracic fascia. The use of meshed vs nonmeshed mucosa to improve the epithelial coverage was examined. We also investigated the creation of a vascular bed over the cartilage and the subsequent application of meshed mucosa. Macroscopic aspects, viability, and degree of mucosal lining were analyzed. SUBJECTS: Twenty male New Zealand white rabbits. INTERVENTIONS: Ten animals underwent placement of auricular cartilage under the laterothoracic fascia. Intact (group 1) or meshed mucosa (group 2) was applied over the fascia and protected by a silicone sheet. After 3 weeks, prefabricated grafts were removed for comparison. In 10 other animals, a sheet of perforated cartilage was placed under the laterothoracic fascia. Two weeks later, 5 grafts (group 3) were harvested. The remaining 5 grafts were reopened for mucosal application over the cartilage and revascularized for 3 additional weeks (group 4). RESULTS: Vascularized plane grafts were obtained in all groups. Mucosal lining increased significantly with meshed mucosa (14%-68%; mean, 40%) compared with nonmeshed mucosa (3%-15%; mean, 10%) (P = .008). Induction of a vascular bed over perforated cartilage was achieved, but survival of secondary implanted mucosa was variable. CONCLUSIONS: A reliable technique to prefabricate composite grafts with cartilaginous support and mucosal lining is presented. The use of meshed mucosa significantly improves epithelial coverage.

Properties of ideal composite knots.

The shortest tube of constant diameter that can form a given knot represents the 'ideal' form of the knot. Ideal knots provide an irreducible representation of the knot, and they have some intriguing mathematical and physical features, including a direct correspondence with the time-averaged shapes of knotted DNA molecules in solution. Here we describe the properties of ideal forms of composite knots-knots obtained by the sequential tying of two or more independent knots (called factor knots) on the same string. We find that the writhe (related to the handedness of crossing points) of composite knots is the sum of that of the ideal forms of the factor knots. By comparing ideal composite knots with simulated configurations of knotted, thermally fluctuating DNA, we conclude that the additivity of writhe applies also to randomly distorted configurations of composite knots and their corresponding factor knots. We show that composite knots with several factor knots may possess distinct structural isomers that can be interconverted only by loosening the knot.

Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury.

BACKGROUND & AIMS Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI. METHODS We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL). RESULTS Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity. CONCLUSIONS When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.

Living-engineered valves for transcatheter venous valve repair.

Background: Chronic venous insufficiency (CVI) represents a major global health problem with increasing prevalence and morbidity. CVI is due to an incompetence of the venous valves, which causes venous reflux and distal venous hypertension. Several studies have focused on the replacement of diseased venous valves using xeno- and allogenic transplants, so far with moderate success due to immunologic and thromboembolic complications. Autologous cell-derived tissue-engineered venous valves (TEVVs) based on fully biodegradable scaffolds could overcome these limitations by providing non-immunogenic, non-thrombogenic constructs with remodeling and growth potential. Methods: Tri- and bicuspid venous valves (n=27) based on polyglycolic acid-poly-4-hydroxybutyrate composite scaffolds, integrated into self-expandable nitinol stents, were engineered from autologous ovine bone-marrow-derived mesenchymal stem cells (BM-MSCs) and endothelialized. After in vitro conditioning in a (flow) pulse duplicator system, the TEVVs were crimped (n=18) and experimentally delivered (n=7). The effects of crimping on the tissue-engineered constructs were investigated using histology, immunohistochemistry, scanning electron microscopy, grating interferometry (GI), and planar fluorescence reflectance imaging. Results: The generated TEVVs showed layered tissue formation with increasing collagen and glycosaminoglycan levels dependent on the duration of in vitro conditioning. After crimping no effects were found on the MSC level in scanning electron microscopy analysis, GI, histology, and extracellular matrix analysis. However, substantial endothelial cell loss was detected after the crimping procedure, which could be reduced by increasing the static conditioning phase. Conclusions: Autologous living small-diameter TEVVs can be successfully fabricated from ovine BM-MSCs using a (flow) pulse duplicator conditioning approach. These constructs hold the potential to overcome the limitations of currently used non-autologous replacement materials and may open new therapeutic concepts for the treatment of CVI in the future.

Evaluation of Composite Pavement Unbonded Overlays: Phases I and II, April 2003

In recent years, thin whitetopping has evolved as a viable rehabilitation technique for deteriorated asphalt cement concrete (ACC) pavements. Numerous projects have been constructed and tested; these projects allow researchers to identify the important elements contributing to the projects’ successes. These elements include surface preparation, overlay thickness, synthetic fiber reinforcement usage, joint spacing, and joint sealing. Although the main factors affecting thin whitetopping performance have been identified by previous research, questions still existed as to the optimum design incorporating these variables. The objective of this research is to investigate the interaction between these variables over time. Laboratory testing and field-testing were planned in order to accomplish the research objective. Laboratory testing involved shear testing of the bond between the portland cement concrete (PCC) overlay and the ACC surface. Field-testing involved falling weight deflectometer deflection responses, measurement of joint faulting and joint opening, and visual distress surveys on the 9.6-mile project. The project was located on Iowa Highway 13 extending north from the city of Manchester, Iowa, to Iowa Highway 3 in Delaware County. Variables investigated included ACC surface preparation, PCC thickness, synthetic fiber reinforcement usage, and joint spacing. This report documents the planning, equipment selection, construction, field changes, and construction concerns of the project built in 2002. The data from this research could be combined with historical data to develop a design specification for the construction of thin, unbonded overlays.

Extratracheal biodegradable splint to treat life-threatening tracheomalacia.

A 9-month-old girl presented with life-threatening acute respiratory failure 1 week after the surgical correction of a double aortic arch, which was due to a severe bulging of the pars membranacea into the lumen of the trachea that produced a complete obstruction of the lower trachea. Under cardiopulmonary bypass, a Y-shaped posterior biodegradable splint was placed behind the trachea and sutured to the posterior trachea, and a simultaneous right aortic arch aortopexy was performed. Thereafter, the child recovered normal respiratory function. Follow-up bronchoscopy showed a posterior dip at the splint level and an asymptomatic persistent posterior compression of the right main bronchus.

[Recueil composite].

Contient : Job, cum commentariis ; Fridegisus, Tractatus de grammatica (34-36). - S. Bonifatius, Ars grammatica (36v-47v, 58-70). - Tatuinus, Ars grammatica (48, 57, 49-56v, 79-86, 71-78v)

Evaluation of Composite Pavement Unbonded Overlays: Phase III, August 2006

In recent years, thin whitetopping has evolved as a viable rehabilitation technique for deteriorated asphalt cement concrete (ACC) pavements. Numerous projects have been constructed and tested, allowing researchers to identify the important elements contributing to the projects’ successes. These elements include surface preparation, overlay thickness, synthetic fiber reinforcement usage, joint spacing, and joint sealing. Although the main factors affecting thin whitetopping performance have been identified by previous research, questions still existed as to the optimum design incorporating these variables. The objective of this research is to investigate the interaction between these variables over time. Laboratory testing and field testing were conducted to achieve the research objectives. Laboratory testing involved shear testing of the bond between the portland cement concrete (PCC) overlay and the ACC surface. Field testing involved falling weight deflectometer deflection responses, measurement of joint faulting and joint opening, and visual distress surveys on the 9.6-mile project. The project was located on Iowa Highway 13 extending north from the city of Manchester, Iowa, to Iowa Highway 3 in Delaware County. Variables investigated include ACC surface preparation, PCC thickness, slab size, synthetic fiber reinforcement usage, and joint spacing. This report documents the planning, construction, and performance of each variable in the time period from summer 2002 through spring 2006. The project has performed well with only minor distress identification since its construction.